Hypercortisolemia is the hallmark symptom in both Cushing disease and Cushing syndrome. Cushing syndrome is the disorder first described by Harvey Cushing in 1932 in several patients with adrenocortical hyperplasia that were the result of basophilic adenomas of the anterior pituitary. Cushing described this syndrome as patients with truncal (central) adiposity, hypertension, weakness, fatigability, purplish abdominal striae ("stretch" marks), amenorrhea, edema, glucosuria, osteoporosis, and hirsuitism. Some confusion can result given that the current distinction between Cushing syndrome and Cushing disease is that the former is associated with adrenal dysfunction (most usually due to tumors) resulting in excess cortisol production and secretion, whereas, the latter results from anterior pituitary dysfunction (most usually due to tumors) resulting in excess ACTH secretion. The excess ACTH over stimulates the adrenal glands resulting, secondarily, in excess cortisol secretion. Sometimes Cushing disease is referred to as ACTH-dependent Cushing syndrome. Considering all cases of hypercortisolemia, 80–85% are caused by pituitary corticotroph adenomas resulting in excess ACTH secretion. The other 10–15% of cases result from unilateral benign and malignant adrenal tumors resulting directly in excessive cortisol secretion.
Central obesity was and continues to be the most common finding in Cushing syndrome. This feature is apparent in approximately 95% of adult patients and in 100% of pediatric patients. In addition to truncal adiposity, Cushing syndrome patients exhibit unique fat accumulations over the face and neck giving the classical "moon" facies and "buffalo hump". In addition to the unique patterns of fat deposition, Cushing syndrome patients have thin extremities (spider appearance) that are due to the effects of cortisol on protein disposition in skeletal muscle. Hypertension is observed in at least 80% of Cushing syndrome patients. This associated hypertension is a major contributing factor to cardiovascular morbidity in this disease. The hypertension in Cushing syndrome results from the effects of glucocorticoids on plasma volume, peripheral vascular resistance, and cardiac output.
Although the hypertension usually improves with surgical removal of the precipitating tumor, patients may still require some form of pharmacologic antihypertensive intervention. This therapy may be required only pre-operatively but is required post-operatively as well in some patient. The thiazides and furosemide can worsen the hypokalemia caused by the excess cortisol and, therefore, should be avoided. The renin-angiotensin system is augmented in Cushing syndrome due to the hypercortisolemia and, therefore, ARBs (angiotensin II receptor blockers) and ACE (angiotensin-converting-enzyme) inhibitors are the recommended drugs of choice to treat hypertension in these patients.
Cushing syndrome patients can manifest with virilization due to the excess cortisol and adrenal androgens. Therefore, women often present with amenorrhea combined with hirsutism, acne, signs of virilization (clitoral enlargement, deepening of the voice, male pattern baldness). Male patients frequently present with diminished libido or impotence associated with subnormal testosterone production.
Screening for Cushing Syndrome
The most common, and recommended, initial tests for Cushing syndrome are urinary free cortisol (UFC) at least two times, late night salivary cortisol, at least two measurements, a 1 mg overnight dexamethasone suppression test (DST), or longer low-dose DST (2 mg/day for 48 hr). Sometimes patient will show normal test results but presented with distinctive clinical features highly suggestive of Cushing syndrome. In these cases it is recommended to periodically repeat the tests.
The gold standard screening test for determination of Cushing syndrome is to assay for ACTH and cortisol levels following a dose of dexamethasone. In this test, a failure to see ACTH and cortisol secretion be suppressed is highly indicative of Cushing syndrome. The 1 mg dexamethasone test is usually given between 11pm and midnight (12am) with cortisol levels being measured between 8am and 9am the following morning. Positive cortisol suppression, in this test, is evident if the serum level is less than 1.8 mg/dl in patients with pituitary causes of Cushing syndrome. In patients with adrenal causes of Cushing syndrome, a positive result is evident with cortisol suppression to 5 mg/dl. In patients with underlying psychiatric disorders (depression, anxiety, obsessive-compulsive disorder) and in patients morbid obesity or in alcoholics the recommended test is the 2 days, 2 mg/day DST assay.
Once hypercortisolemia is diagosed, its cause needs to be identified. An ACTH level is the next step to further investigate the source of Cushing syndrome. ACTH levels below 5 pg/ml at two separate occasions support the diagnosis of ACTH-independent Cushing disease. If serum ACTH is more than 15 pg/ml the disease is most likely to be ACTH-dependent Cushing syndrome.
Treatment of Cushing Syndrome
Surgery is the preferred treatment for both ACTH-dependent and -independent Cushing syndrome. In patients with Cushing disease, the initial treatment is selective pituitary adenomectomy. Post-operative hypocortisolemia is the measure for surgical success and this varies between 70% and 90%. In patients with persistent or recurrent disease in it is necessary to carry out transsphenoidal surgery and add radiation therapy. In addition, it is often recommended to include bilateral adrenalectomy as a definitive treatment option that provides immediate control of hypercortisolemia. Although recommended in many cases, this latter surgical approach is not without potential for serious complications in addition to the problem of patient compliance with lifelong glucocorticoid and mineralocorticoid replacement therapy. Patients who undergo bilateral adrenalectomy are at risk for Nelson syndrome. Nelson syndrome is growth of a pituitary corticotroph adenoma which can cause neurologic symptoms due to compression from the mass and also lead to increased ACTH secretion.
Following surgical intervention, Cushing syndrome patients require pharmacological management that is usually directed at decreasing adrenal steroid secretion. Steroidogenesis inhibitors like metyrapone, ketoconazole aminoglutethimide, and etomidate have been successfully used to lower cortisol level. Metyrapone is effective in controlling in 80% of patients with Cushing’s disease and adrenal tumor. Adrenal insufficiency is the major unwanted effect. In addition, hirsutism and acne may worsen in patients due to the accumulation of androgenic precursors from metyrapone blockade of cortisol synthesis. Ketaconazole is an oral antimycotic that when taken in larger doses inhibits cortisol synthesis. An advantage to ketaconazole is that adrenal androgen concentrations and serum cholesterol concentrations fall, whereas, they rise with metyrapone treatment. Aminoglutethimide blocks adrenal synthesis of cortisol, aldosterone, and androgens, as well as the production of estrogens in extraglandular tissues. Etomidate, normally used as an anesthetic, is a potent inhibitor of cortisol secretion when administered parenterally at low doses. Mifepristone is a synthetic steroid with high affinity for both the glucocorticoid and the progesterone receptors. Administration of mifepristone leads to inhibition of glucocorticoid receptor activation and, as a result, inhibition of transcriptional activation of cortisol target genes.